This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The inadequate delivery of chemotherapeutics to the desired site of action in the brain results in a poor response to drug treatment for many neurological disorders (i.e., Alzheimer's disease, brain tumors, HIV, and other genetic disorders). The blood[unreadable]brain barrier (BBB) regulates the influx and efflux of a wide variety of substances and remains the major obstacle of delivery of pharmaceutics into the central nervous system (CNS). The development of BBB targeting strategies is a very active field of research and includes manipulation of the drug, modification of capillary permeability of the BBB, or attempts to increase the driving force for transport by increasing plasma concentrations of the drug (i.e., high-dose chemotherapy, intra-arterial injection). We have been successful in demonstrating that chemical modification of a highly lipophilic non-permeable p-glycoprotein (P-gp) substrate (i.e., paclitaxel [Taxol[unreadable]]) can be achieved, resulting in increased permeability through the BBB, and that targeting active drug transporter vector systems is viable. Our long-term objectives are to (1) demonstrate that through the utilization of combinatorial chemistry we can successfully synthesize new pharmacologically active derivatives of anticancer moieties with enhanced permeability, (2) characterize active transporters at the BBB with known vectors that may be useful in explaining the mechanistic pathways of the analogues, and (3) demonstrate an in vitro/in situ correlation of the mechanistic pathways of a derivative's enhanced permeability. Knowledge of these mechanisms should lead to strategies that may be employed to enhance therapeutic delivery of pharmaceuticals to the brain. The specific aims of this project will be: 1. Devise a computational model to study structure[unreadable]activity relationships of P-gp substrates. 2. Synthesize derivatives based on the predictive parameters from computational modeling. 3. Determine uptake and permeability properties of new analogues utilizing an in vitro cell culture model of the BBB and develop an analytical method of detection of new analogues. 4. Determine the mechanism of transport to explain enhanced uptake and permeability of compounds with reduced P-gp affinity.